1. Field of the Invention
This invention relates to the production and recovery of alkaloid compounds known to be present in the tissues of the evergreen plant, Cephalotaxus harringtonia, and known to be active against lymphocytic leukemia in test mice. This invention also relates to the production of a novel alkaloid compound not previously identified in C. harringtonia plant material.
2. Description of the Prior Art
Among the alkaloids which have been isolated from C. harringtonia plant material are cephalotaxine and a number of its esters [Powell et al., Tetrahedron Lett. 4081 (1969); Powell et al., Tetrahedron Lett. 815 (1970); and Mikolajczak et al., Tetrahedron 28: 1995 (1972)]. Though cephalotaxine itself is inactive, some of its esters which are derived from relatively complex dicarboxylic moieties have been found to exhibit significant antitumor activity against lymphoid leukemia L1210 and P388 leukemia in mice [Powell et al., J. Pharm. Sci. 61(8): 1227-1230 (August 1972)]. Two of the esters, harringtonine and homoharringtonine, have been approved for preclinical evaluation at the National Cancer Institute. Continued biological testing of the active esters requires quantities which cannot be supplied by the relatively scarce natural sources.
Various active alkaloids have been produced synthetically. The preparation of deoxyharringtonine is taught by Mikolajczak et al. in U.S. Pat. No. 3,959,312 and natural (-) cephalotaxine has been esterified with a number of synthetic acids [Mikolajczak et al., J. Med. Chem. 20: 328 (1977)]. However, the yield and stereochemical purity from these synthetic techniques is not sufficiently high to provide a practical source of active esters.